This act failed to satisfy either side. All sides took offence at the Emperor openly dictating church doctrine, although the Patriarch of Antioch was pressured into subscribing to the Henotikon. When Patriarch John I of Alexandria refused, the Emperor had him expelled and instead recognized the Miaphysite Peter Mongos, who accepted the Henotikon. However, other monophysites abandoned him and were thenceforth called Akephaloi (headless ones), since they had lost their leader.[2] After two years of prevarication and temporizing by Acacius, Pope Felix III of Rome condemned the act and excommunicated Acacius (484), although this was largely ignored in Constantinople, even after the death of Acacius in 489.

Zeno died in 491. His successor Anastasius I was sympathetic to the monophysites, and accepted the Henotikon. However, Anastasius's position was at odds with the predominantly Chalcedonian population of Constantinople, and Vitalian, a Chalcedonian general, attempted to overthrow him in 514. Anastasius then attempted to heal the schism with Pope Hormisdas, but this failed when Anastasius refused to recognize the excommunication of the now deceased Acacius. Vitalian tried to overthrow the emperor a second time, but he was defeated by loyal officers.

The schism caused by the Henotikon was officially settled in 519 when Emperor Justin I recognized the excommunication of Acacius and reunited the churches. However, the then-Patriarchs of Alexandria and Antioch still embraced miaphysitism, and their congregations came to be known in modern times as the Oriental Orthodox Churches. Meanwhile, the incident did nothing to mend the growing rift between the churches of Constantinople and Rome, which would lead in the centuries to come to the East-West Schism.